Substance abuse accounts for a high number of preventable illnesses and deaths each year and places a significant social and financial toll on individuals and society. Presently, for example, there are no FDA-approved medications to treat cocaine addiction. Drugs of abuse produce their reinforcing effect through actions in the limbic component of the basal ganglia. With repeated use, drugs of abuse can cause long term changes in the brain's reward circuit. Specifically repeated exposure leads to profound changes in glutamate transmission in limbic nuclei, particularly the nucleus accumbens.
TNFα has been associated with the rewarding effects of methamphetamine. Exposure to methamphetamines results in glial activation and increases in TNFα level9-11. Cocaine administration results in upregulation of inflammatory signals, including TNFα12. Morphine and ethanol activate glia directly via the Toll-Like Receptor 4 (TLR4) and increase inflammatory signals including TNFα13,14. There are conflicting data on the role of TNFα in addiction-related behaviors. Narita et al. suggest that TNFα contributes to the rewarding effect of these drugs15, while the Nabeshima group suggests that TNFα administration suppresses the rewarding effects of either drug9,16,17.
Monophosphoryl lipid A (MPLA) is a Toll-like receptor 4 agonist commonly used as a nontoxic, FDA-approved adjuvant in vaccines. Also liposomes containing MPLA have been reported as a potent adjuvant system for inducing antibodies to heroin hapten analogs22.